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Corticosteroids and the risk of atrial fibrillation. |
High-Dose Steroids Linked to Risk of Atrial Fibrillation | MedPage Today
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Akiko Shiroshita-Takeshita, Bianca J. This study evaluated the efficacy of anti-inflammatory and calcineurin-inhibitory drugs on promotion of atrial fibrillation by atrial tachycardia-induced remodeling in dogs. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. A final open-chest study was performed on day 8.
In addition, prednisone but not ibuprofen or cyclosporine significantly decreased C-reactive protein concentrations and attenuated the increase in endothelial nitric oxide synthase expression caused by atrial tachypacing.
Conclusions: Prednisone prevents the electrophysiological and atrial fibrillation-promoting effects of atrial tachycardia-remodeling, possibly by an anti-inflammatory action, whereas the less potent anti-inflammatory ibuprofen and the calcineurin inhibitor cyclosporine-A are without effect. Atrial fibrillation AF is the most common arrhythmia in clinical practice. Drug therapy for AF is presently suboptimal and there is interest in developing novel approaches that target specific mechanistic determinants [1].
A role for inflammation was first suggested based on observations in postoperative AF [2]. The time of peak AF occurrence second to third postoperative day coincides with peak concentrations of the inflammatory marker, C-reactive protein CRP [2]. CRP concentrations are also a predictor of future AF [5]. A small clinical trial indicated that methylprednisolone therapy can prevent AF recurrence, supporting a potential role for inflammation in AF [6]. AF remodels atrial electrophysiology in a way that favors AF maintenance and increases vulnerability to recurrence should AF terminate [7—10] , an effect attributable principally to atrial tachycardia [1,8,10].
There is evidence that this process is important in AF pathophysiology, and suppressing it may contribute to the clinical efficacy of amiodarone [11]. Simvastatin, which has anti-inflammatory properties, suppresses atrial-tachycardia remodeling [12]. We wondered whether anti-inflammatory agents, such as glucocorticoids, might also suppress atrial-tachycardia remodeling. We therefore designed this study to assess the effects of prednisone and the non-steroidal anti-inflammatory drug ibuprofen on the electrophysiological consequences of atrial tachycardia in dogs.
In addition, evidence has been presented for calcineurin activation as a signal transduction pathway in porcine tachycardia-induced AF [13] and in tissue from AF patients [14]. We therefore added an additional group of dogs to determine the effect on atrial-tachycardia remodeling of inhibiting calcineurin-signaling with the calcineurin-antagonist agent cyclosporine-A.
Animal-handling procedures followed guidelines of the National Institutes of Health. Forty-two mongrel dogs 20—37 kg were anesthetized with ketamine 5. Unipolar pacing leads were inserted through jugular veins into the right ventricular RV apex and right atrial RA appendage under fluoroscopic guidance, and were connected to pacemakers Vitatron, USA in subcutaneous pockets in the neck.
A bipolar electrode was inserted into the RA for stimulation and recording during serial closed-chest electrophysiological studies EPSs. Atrioventricular block was created by radiofrequency-catheter ablation to avoid excessively rapid ventricular responses during atrial tachypacing ATP. The RV demand-pacemaker was programmed to 80 bpm. After h post-operative recovery, a baseline closed-chest EPS was performed and then 7-day ATP at bpm was instituted. All drugs were given orally in 2 divided doses, started 3 days prior to ATP onset and continued until the morning of the final open-chest EPS.
We used a larger number of non-paced and ATP dogs than in the drug-intervention groups because we performed concomitant controls for each intervention series.
For closed-chest EPS, dogs were anesthetized with ketamine 5. The atrial tachypacemaker was deactivated and effective refractory period ERP of the RA appendage was measured at basic cycle lengths BCLs of , , , , and ms with 10 basic stimuli S1 followed by premature extrastimuli S2s with 5-ms decrements.
All stimuli were twice-threshold, 2-ms pulses. A min rest period was then allowed before continuing measurements. If prolonged AF was induced twice, no further AF induction was performed. A median sternotomy was performed, and bipolar electrodes were hooked into the RA and left atrial LA appendages for recording and stimulation.
Silicon sheets containing bipolar electrodes were attached to the atria as previously described [10—12]. AF vulnerability was determined as the percentage of atrial sites at which AF was induced by single extrastimuli.
Serum ibuprofen concentration was analyzed by high-performance liquid chromatography with an LCDB column and ultraviolet detection nm, Mayo Medical Laboratories. Tissue samples were homogenized in Radio-immuno-precipitation assay buffer as previously described [15]. Horseradish peroxidase-conjugated anti-mouse IgG Santa Cruz Biotechnology was the secondary antibody.
Protein was loaded in the linear immunoreactive-signal range and target-band intensities expressed relative to GAPDH intensity from the same sample. AF duration and CRP data were analyzed after normalization by logarithmic transformation. Bonferroni-corrected t -tests were applied to evaluate individual mean differences when ANOVA revealed significant group effects.
There were no significant differences in ERPs among groups at baseline day 0. ERP decreased slightly in prednisone-treated dogs, but the changes were much smaller than in ATP-only dogs. Although lower-dose prednisone produced slightly smaller effects than higher-dose, both resulted in ERPs significantly greater than AT-only. The loss of ERP rate-adaptation in ibuprofen- Fig. Time course of atrial tachypacing-induced changes in ERP rate-adaptation during serial closed-chest electrophysiological studies.
ERP rate-adaptation was better preserved during the study period despite atrial tachypacing in prednisone-treated dogs B. Group abbreviations are as in Fig. ATP during treatment with ibuprofen Fig. No significant increase in DAF was observed in prednisone-treated dogs.
There were no significant differences among groups in body weight or hemodynamic variables at final open-chest study, although systolic pressures tended to be higher in the high-dose prednisone group Table 1.
The mean day-7 trough ibuprofen serum concentration was No significant differences were observed between ATP-only dogs and ibuprofen-treated or cyclosporine-A-treated dogs. For reference, results are shown in each panel for non-paced dogs NP and from atrial tachypaced dogs that did not receive drug therapy ATP. However, ERP rate-adaptation was preserved in prednisone-treated dogs. ERP rate-adaptation was significantly decreased in dogs subjected to atrial tachypacing without drug therapy ATP.
ERP rate-adaptation was relatively preserved not significantly different from non-paced NP dogs in both atria of prednisone-treated dogs. Bottom: Indices of AF promotion at the final open-chest study. D: AF vulnerability percentage of atrial sites at which AF could be induced by single extrastimuli. Abbreviations as in Fig. In non-paced control dogs, AF was generally short-lasting and always terminated spontaneously within 5 min. No prolonged AF requiring cardioversion occurred in prednisone-treated dogs.
ATP dogs treated with ibuprofen or cyclosporine-A demonstrated increased AF duration relative to non-paced controls, to the range of — s, not significantly different from ATP-only dogs. ATP-induced increases in AF duration were significantly attenuated in prednisone-treated dogs. There were no significant CRP differences among groups on day 0 Fig. CRP values in various experimental groups on day 0 P0 , immediately prior to tachypacing onset A , and on day 7 P7 of tachypacing B.
CRP was not significantly different among study groups on day 0. Neither ibuprofen nor cyclosporine-A significantly altered the ATP effect. ATP-only dogs. Western-blot data are available only for high-dose prednisone experiments PDN. In this study, we evaluated the effects of prednisone, ibuprofen, and cyclosporine-A on atrial remodeling due to 1 week of atrial tachycardia.
We found that prednisone suppresses both the electrophysiological consequences of atrial tachycardia remodeling and the associated AF promotion, whereas ibuprofen and cyclosporine-A are without effect. Prednisone's anti-remodeling properties were associated with significant CRP reduction and attenuation of tachycardia-induced eNOS activation. Atrial tachyarrhythmias alter atrial electrophysiology, shortening ERP, reducing ERP rate-adaptation and promoting AF occurrence and maintenance [7—10].
Because of clinical evidence for the importance of atrial tachycardia remodeling in the pathophysiology of AF, there have been considerable efforts to define its pathophysiology with an eye to developing pharmacological approaches to its prevention [1]. Calcium overload in cardiomyocytes is considered to play an important role in initiating the process of atrial remodeling [18,19] , subsequently leading to atrial ionic, molecular, contractile and ultrastructural changes [20—24].
A number of studies have been performed to pursue pharmacologic approaches to prevent atrial remodeling. Simvastatin prevents atrial tachycardia-induced remodeling in dogs, an effect that could be related to an anti-inflammatory action [12]. In addition, atorvastatin prevents AF induced in the presence of sterile pericarditis in dogs, while decreasing CRP concentrations [29]. The present study is the first of which we are aware showing that glucocorticoids prevent tachycardia-induced remodeling in association with reduced CRP concentrations, and providing one possible mechanism for the results of studies indicating AF suppression by oral glucocorticoid therapy [6,30].
There is evidence for a role of inflammation in several forms of AF. Postoperative AF is associated with CRP increases and complement activation [2] , and baseline CRP concentrations are a predictor of postoperative AF for both on-pump and off-pump surgery [31].
CRP concentrations are higher in patients with AF than in sinus rhythm patients [4] , and there is an epidemiological association between CRP concentrations and AF prevalence at baseline as well as with AF risk on follow-up [5]. The present study supports a role for inflammatory changes in AF pathophysiology, by indicating that the potent anti-inflammatory compound prednisone suppresses atrial tachycardia remodeling in association with decreased CRP concentrations.
The anti-inflammatory action of NSAIDs is due only to cyclooxygenase inhibition, whereas glucocorticoids act via a variety of mechanisms including redirection of leukocytes and suppression of inflammatory cytokines and leukocyte adhesion molecules [33,34]. Our results are consistent with previous clinical observations of steroid efficacy in AF prevention [6,30] , as well as with a recent study showing beneficial effects of glucocorticoids in a model of post-cardiac surgical AF [35].
However, although the present findings are consistent with a role for inflammation in atrial tachycardia remodeling, they do not constitute proof of the notion. Calcineurin enzyme activity is activated and expression of the downstream signal nuclear factor of activated thymocytes NFAT is augmented in pigs subjected to 6 weeks of atrial tachypacing [13].
Based on this information, we speculated that the calcineurin inhibitor cyclosporine-A would inhibit atrial tachycardia remodeling. However, we were unable to demonstrate any protective effect of cyclosporine-A against atrial tachycardia-induced changes. Enhanced nitric oxide production can alter transcriptional mechanisms and contribute to inflammatory processes [36].
Barouch et al. This study is to our knowledge the first to assess the effects of glucocorticoids, NSAIDs or calcineurin inhibitors in an animal model of AF promotion by atrial tachycardia.
Our results show that prednisone, but not ibuprofen or cyclosporine-A, suppresses atrial tachycardia-induced electrical remodeling and AF promotion.
The suppression by prednisone of CRP and eNOS levels may provide potential insights into mechanisms underlying prednisone's actions. This information is relevant to the pharmacological suppression of atrial remodeling and the development of new approaches to AF prevention, and suggests one potential candidate mechanism for previous observations of glucocorticoid efficacy in AF management [6,30].
In contrast to our results, Cai et al. However, Carnes et al.
❾-50%}- Prednisone and afib
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Background: High-dose pulse corticosteroid therapy has been associated with the development of atrial fibrillation. This association, however, is mainly based on case reports. Methods: To test the hypothesis that high-dose corticosteroid exposure increases the risk of new-onset atrial fibrillation, we performed a nested case-control study within the Rotterdam Study, a population-based cohort study among older adults.
Cases were defined as persons with incident atrial fibrillation between July 1,and January 1, Their date of diagnosis was defined as the index date. All noncases within the Rotterdam Study who were alive and eligible on this index date were used as controls.
Subsequently, we compared the proportion of cases and controls that received a corticosteroid prescription within 1 month preceding the index date. Results: There were eligible cases of new-onset atrial fibrillation during the study period. The risk of new-onset atrial fibrillation was significantly higher for persons who received a corticosteroid prescription within 1 month before the index date than for those without odds ratio [OR], 3.
However, only high-dose corticosteroid use was associated with an increased risk OR, 6. The association of atrial fibrillation with high-dose corticosteroid use was largely independent of the indication for corticosteroid therapy, since the risk of new-onset atrial fibrillation was not only increased in patients with asthma or chronic obstructive pulmonary disease OR, 4.
Conclusion: Our findings strongly suggest that patients receiving high-dose corticosteroid therapy are at increased risk of developing atrial fibrillation. Abstract Background: High-dose pulse corticosteroid therapy has been associated with the development of atrial fibrillation.
Substances Adrenal Cortex Hormones.
Atrial tachycardia-induced electrophysiological remodeling and AF promotion are prevented by therapy with prednisone, but not by ibuprofen or cyclosporine-A. A daily dose of at least mg of prednisone equivalents was associated with a six-fold increase in risk of new onset atrial fibrillation, Cornelis S. van. A daily dose of at least mg of prednisone equivalents was associated with a six-fold increase in risk of new onset atrial fibrillation, Cornelis S. van. High-dose (pulse) glucocorticoid therapy can induce atrial fibrillation, as demonstrated in several case reports [29,30] and a Dutch nested. Background: High-dose (pulse) corticosteroid therapy has been associated with the development of atrial fibrillation. Chang M. Dobrev D. AF remodels atrial electrophysiology in a way that favors AF maintenance and increases vulnerability to recurrence should AF terminate [7—10]an effect attributable principally to atrial tachycardia [1,8,10].A daily dose of at least 7. There was, however, no observed increase in the risk of atrial fibrillation among patients treated with low or intermediate doses of corticosteroids. These data emerged from a nested case-control study within the Rotterdam Study, an ongoing population-based cohort study of 7, residents of Ommoord, a Rotterdam suburb.
All participants were 55 or older at baseline in Participants underwent follow-up examinations every four to five years. Corticosteroid use was tracked by computerized pharmacy records. The study endpoint was atrial fibrillation, death, or the end of the study period, which was Jan. During the follow-up the researchers identified patients with new onset atrial fibrillation, which were included in the analysis.
Those cases were compared with 6, controls. High-dose corticosteroid use was associated with an odds ratio of 6. Because patients taking high-dose corticosteroids had other risk factors for atrial fibrillation, the authors performed two additional analyses.
For the high dose in other disease group, the OR became 9. They then divided the cases into two groups--those with zero to two risk factors for atrial fibrillation and those with three or more risk factors. Then they analyzed the data again. Using that risk stratified model, they found that among patients with zero to two risk factors who took high-dose corticosteroids the OR was 7. The study findings triggered an immediate response from the American Heart Association, which issued a statement warning that patients taking corticosteroids should "not immediately stop taking them," said Kenneth Ellenbogen, M.
He warned that abrupt cessation of corticosteroid therapy can trigger adrenal crisis. That said, Dr. Such monitoring, they wrote, "could increase the chance to diagnose and treat this serious arrhythmia as early as possible. Share on Facebook. Opens in a new tab or window. Share on Twitter. Share on LinkedIn. Action Points Explain to patients who ask that the results of this study suggest that high-dose corticosteroid therapy may increase the risk of atrial fibrillation.
Explain that concerned patients should not immediately stop corticosteroid therapy as this may trigger a number of serious side effects and doses should be carefully managed by physicians. This study suggests that careful monitoring of these patients by clinical examination and by performing an ECG before and after high-dose pulse therapy is warranted to detect atrial fibrillation.
The American Heart Association issued a statement warning that patients taking corticosteroids should "not immediately stop taking them.
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